The compound (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, having the structure:
is also known as SNS-595 or AG-7352. The United States Adopted Names Council (USANC) has assigned the name “Voreloxin” to this compound.
SNS-595 is known for its anti-tumor activity (see, Tsuzuki et al., J. Med. Chem., 47:2097-2106, 2004 and Tomita et al., J. Med. Chem., 45:5564-5575, 2002). Treatment of various cancers with SNS-595 has been proposed in the literature, and has shown preclinical activity against various cancer cell lines and xenografts. Various dosing regimens for the use of this compound have been reported. For example, see U.S. Patent Application Pub. Nos. 2005-0203120 A1: 2005-0215583 A1 and 2006-0025437 A1, all of which are incorporated herein by reference in their entireties. SNS-595 is presently being tested in clinical trials to assess safety and efficacy in human cancer patients, and has demonstrated clinical activity against acute myeloid leukemia and ovarian cancer.
SNS-595 can be prepared using techniques known to one of skill in the art. See, for example, U.S. Pat. No. 5,817,669, issued Oct. 6, 1998, Japanese Patent Application No. Hei 10-173986, published Jun. 26, 1998, WO 2007/146335, Tsuzuki et al., J. Med. Chem., 47:2097-2106, 2004 and Tomita et al., J. Med. Chem., 45: 5564-5575, 2002, which are incorporated herein by reference in their entirety.
Conventional methods of preparing SNS-595 can yield compositions comprising other compounds that either result from side reactions that occur during the SNS-595 synthesis process or are reagents that remain unreacted.
International patent application WO 2007/146335, published Dec. 21, 2007, describes preparation of a composition that comprises SNS-595 and (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-amino-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, which is described therein as an “N-desmethyl” compound. Data are presented indicating that the N-desmethyl compound is shown to be active in a cytotoxicity assay. The N-desmethyl compound is a significant side product of the conventional approach to synthesizing SNS-595.
Thus, there remains a need for improved methods for preparing SNS-595 substantially free of contaminants, to provide the compound in a substantially pure form well suited for formulation into pharmaceutical compositions for the treatment of cancer without the need for laborious purification steps.